Background: An estimated 31% of HIV-infected (HIV+) individuals in the United States are aged 50 or older. These individuals are at heightened risk of functional decline due to physiological mechanisms that contribute to increased inflammation and alterations in body composition even after effective antiretroviral treatment. Over time, this may contribute to persistently elevated metabolic rate and decreased availability of energy for daily physical activities, as a greater proportion of energy is needed to combat comorbid conditions and repair cellular damage. Recent evidence indicates that in the older, less resilient population, this may accelerate the onset of frailty, disability, and death. Methods To assess and quantify the accelerated onset and temporal dynamics of functional decline in the aging HIV-infected population, we propose to assess gait speed, resting metabolic rate, walking energy expenditure, and objectively measured physical activity in virologically suppressed HIV+ and HIV- men in the Baltimore Multicenter AIDS Cohort Study (MACS). We hypothesize that: (i) gait speed will be slower in HIV+ men and will decrease faster with age relative to HIV- men, (ii) energy expenditure at rest and during standard walking (O2 consumption and CO2 production) will both be elevated in HIV+ men relative to HIV- men, (iii) the association between higher energy expenditure and slower gait speed will be mediated by higher levels of inflammatory markers (e.g., IL-6) and lower lean mass, (iv) HIV+ men will exhibit lower cumulative daily physical activity with more pronounced evidence of fatigue-driven activity patterns than HIV- men, and (v) HIV+ men will have lower day-to-day variability and complexity of circadian rhythms of activity relative to HIV- men. Output: The data obtained from this research will provide critical insight into (i) the amount of excess energy needed for independent living in those with treated HIV infection, and (ii) the associated threats to physical activity an functional mobility. We will use these data as the basis for a future R01 submission designed to: (i) longitudinally evaluate energy expenditure at rest and during walking as causal biomarkers of functional health status and (ii) provide evidence for interventions aimed at: (a) increasing walking efficiency by lowering energy costs through rehabilitative therapy to improve body composition and/or altered drug regimens to lower inflammation, and (b) increasing physical activity and reducing fatigue by targeting low-points of daily activity through analysis of circadin activity patterns. This will contribute to improved function and reduced risk of frailty, disabilit, and death in aging HIV populations.